The morbidity rate of coronary artery disease has recently increased in Japan. This is attributable to changes from traditional to more westernized lifestyles. In this study, we therefore examined the risk factors and predictors of coronary arterial lesions in Japanese patients with essential hypertension. Coronary angiography was performed in 109 consecutive essential hypertension patients (57 men and 52 women; 66±8.0 years of age) with either angina pectoris or atypical chest pain, who were chosen from 485 consecutive hypertensive patients in a hypertension clinic in Sendai, Japan. Coronary arterial stenosis of greater than 50% was defined as significant and used as a dependent variable for the multiple regression analysis. Risk factors were defined as factors confirmed to have a causal relationship with coronary arterial lesions, whereas arteriosclerotic complications and hypertensive target organ damage were defined as predictors. Multiple logistic regression analysis was performed using these parameters as independent variables. Of 109 patients, 25 had a coronary arterial stenosis greater than 50%. A smoking habit (odds ratio (OR): 4.48; 95% confidence interval (CI): 1.13-17.82; p<0.05), hypercholesterolemia (OR: 5.34; 95% Cl: 1.52-18.73; p<0.05), and 24-h diastolic blood pressure (OR: 2.33; 95% Cl: 1.06-5.16; p<0.05) were significant risk factors, whereas carotid intima-media thickness (OR: 5.85; 95% Cl: 1.48-23.2; p<0.05) was a significant predictor of coronary arterial lesion. When two of the major risk factors (a smoking habit, hypercholesterolemia, or impaired glucose tolerance including diabetes mellitus) were clustered in addition to the hypertension, the risk of coronary arterial lesions increased by 6.7 to 10.1 times. These findings indicate that the major risk factors established in Caucasians, I.e., a smoking habit, hypercholesterolemia and blood pressure level, are also risk factors for coronary arterial lesions in Japanese with essential hypertension. The presence of two or more risk factors increases the risk of coronary arterial lesions synergistically in the presence of hypertension. (Hypertens Res 2001; 24: 3-11)

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The present study was carried out to investigate whether the renal resistive index (RRI), obtained by ultrasonic duplex scanning, is useful for the evaluation of renal arteriosclerosis in essential hypertensive patients. We also studied the relationships between RRI and other kinds of hypertensive target-organ damage, including carotid atherosclerosis. One hundred and two patients (56.4±9.4 years) with untreated mild or moderate essential hypertension were examined. The normal range of RRI was determined for 12 normal age-matched volunteers (55.0±6.6 years). Hypertensive organ damage was evaluated by funduscopy, electrocardiograms, and carotid B-mode imaging. Based on the mean and distribution of RRI in normal volunteers (0.60±0.05), the normal upper limit of RRI was found to be 0.7. RRI was correlated with creatinine clearance (CCr)(r=−0.61, p<0.05), and blood urea nitrogen (r=0.46, p<0.05), but not with serum creatinine. In addition, the incidence of abnormal RRI (>0.7) was higher in patients with left ventricular hypertrophy and in those with advanced carotid atherosclerosis (p<0.01, respectively). Thus, RRI appears to be more strongly associated with CCr than with serum creatinine, and it increases in patients with hypertensive end-organ damage. The assessment of RRI may be useful for the evaluation of early renal damage in essential hypertension. (Hypertens Res 2001; 24: 13-17)

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We investigated the relationship between 24-h blood pressure (BP) and cognitive function. We performed the Hasegawa Dementia Scale Revised (HDSR), the Mini-Mental State Examination (MMSE), and the Raven’s Coloured Progressive Matrices Test (RCPM) in 88 subjects (71±9 years) with no history of stroke. Ambulatory BP was non-invasively measured using a TM2421 for 24h in all patients. Whereas 90% of the scores converged into a narrow range between 25 and 30 points in the HDSR and the MMSE tests, the RCPM score was widely distributed, ranging from 9 to 36 points. The subjects were therefore divided into three groups of ≥25, 26-30, and 31-36 according to their RCPM scores. Subjects with lower scores were significantly associated with increased short-term BP variability during the daytime (p<0.05) and had a tendency toward higher nighttime SBP (p=0.05) compared with those with higher scores. Increased short-term variability of daytime BP and high nighttime systolic BP were associated with cognitive impairment as assessed by the RCPM. The RCPM, which can assess the capacity for judgment through visual information processing, may detect earlier stages of cognitive impairment related to high BP. To prevent a deterioration of cognitive function, strict control of nighttime BP and suppression of short-term BP variability are thus necessary. (Hypertens Res 2001; 24: 19-24)

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Night shift work has often been associated with increasing degree and frequency of various psychologic complaints. The study examined whether psychologic states after night work are related to adaptive alterations of the cardiovascular and neuroendocrine systems. We studied 18 healthy nurses (age 29±2 years) engaged in a modified rapid shift rotation system (day work, 8:15-17:15; evening work, 16:00-22:00; night work, 21:30-8:30). Blood pressure, heart rate, RR interval variability (L/H and HF power spectrum for sympathetic and vagal activities), and physical activity were measured using a multibiomedical recorder for 24h from the start of work during the night and day shifts. Plasma ACTH and cortisol concentrations were measured at the end of each shift and at 8:30 AM on a day of rest. Each subject’s psychologic state was assessed using a validated questionnaire. Among the parameters measured, scores for confusion, depression, anger-hostility, fatigue and tension-anxiety were highest, and scores for vigor lowest, after a night shift. Systolic blood pressure and heart rate during work were lower during night shift than during day shift (119±2 vs. 123±1mmHg, p<0.05 and 75±1 vs. 84±2bpm, p<0.001, respectively). Both parameters were lower still (p<0.005 and p<0.05) when measured outside of the hospital under waking conditions following a night shift than following a day shift, even though the levels of physical activity were similar. The HF power spectrum of RR interval variability was greater not only during work (24.2±2.1 vs. 18.5±1.8ms, p<0.005) but also during the awake period (29.1±2.5 vs. 24.4±2.6ms, p<0.005) after the night shift compared with the day shift. Plasma ACTH and cortisol concentrations were lower after night work than in the day of rest(7.3±1.2 vs. 11.5±2.3pg/ml, p<0.1 and 11.1±1.1 vs. 14.4±1.1mg/dl, p<0.05). Systolic and diastolic blood pressures during night shift work and the subsequent awake period correlated positively with scores for vigor and negatively with scores for confusion (p<0.05). Plasma ACTH and cortisol concentrations did not correlate with any psychologic scores. We conclude that psychologic disturbances after night work were associated with altered cardiovascular and endocrine responses in healthy nurses. Some of the psychologic complaints may be attributable to lower waking blood pressure. (Hypertens Res 2001; 24: 25-31)

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11β-Hydroxysteroid dehydrogenases (11β-HSD) interconvert cortisol, the physiological glucocorticoid, and its inactive metabolite cortisone in humans. There are two isoforms. The type 1 isoform (11β-HSD1) catalyzes both 11β-dehydrogenation (cortisol to cortisone) and the reverse oxoreduction (cortisone to cortisol), but the type 2 isoform (11β-HSD2) catalyzes only 11β-dehydrogenation. The diminished dehydrogenase activity has been demonstrated in resistance vessels of genetically hypertensive rats. However, the isoform(s) that plays a significant role in conferring the dehydrogenase activity on vasculature has not been determined. We investigated 11β-HSD activities in human vascular smooth muscle cells by manipulating 11β-HSD expressions with antisense oligonucleotides. The results showed that 11β-HSD2 dominates functioning in the dehydrogenase mode in these cells. This indicates that impairment of 11β-HSD2 activity in vascular wall may be related to the pathogenesis of hypertension. (Hypertens Res 2001; 24: 33-37)

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We examined the role of the central nervous system, and particularly the renin-angiotensin (RA) system, in the development of hypertension produced by chronic inhibition of NO synthesis. In experiment 1, Wistar rats drank either nitro-L-arginine-methyl ester (L-NAME) or tap water. Before L-NAME treatment rats were divided into 6 groups. Four of them were administered either losartan or artificial cerebroventricular fluid (a-CSF) intracerebroventricularly (i.c.v.) for 1 week using an osmotic mini pump. The other two groups were administered the same amount of losartan intravenously (i.v.). In experiment 2, cardiovascular responses to acute i.c.v. losartan and muscimol, a GABA_A agonist, were examined in conscious L-NAME-treated rats. Finally, in experiment 3, effects of ablation of the AV3V (anteroventral third ventricle) area, known to be one of the centers of cardiovascular control, were tested in the development of L-NAME hypertension. The development of hypertension by L-NAME treatment was attenuated with chronic i.c.v. losartan in a dose-dependent manner, while i.v. losartan had no effect. One week after cessation of i.c.v. losartan, blood pressure was elevated to the same level as in a-CSF-infused, L-NAME-treated rats. Acute i.c.v. losartan produced no cardiovascular changes in either L-NAME-treated or control rats. On the other hand, although i.c.v. muscimol elicited depressor effects in both groups, these responses were significantly larger in L-NAME-treated rats. Cardiovascular responses to i.v. hexamethonium were similar in both groups. The existence of prior lesions in the AV3V area significantly attenuated the development of L-NAME-induced hypertension. These results indicate that the central RA system plays an important role in the development of hypertension produced by chronic inhibition of NO synthase. Moreover, disorder of the central GABA system, rather than that of the RA system, might be important in the maintenance of hypertension in this model. (Hypertens Res 2001; 24: 39-45)

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Cerebral arteries are innervated by nitric oxide (NO)-mediated vasodilator nerves, and hypoxia has been shown to attenuate neurogenic vasorelaxation. The present study examines the effects of hypothermia on neurogenic vasorelaxation and on the hypoxia-induced inhibition of the neurogenic vasorelaxation response. In isolated canine cerebral arteries, relaxant responses to transmural electrical stimulation (5 Hz for 40 s), mediated via NO synthesized from L-arginine, were not influenced by lowering the bathing media temperature from 37°C to 30°C but were attenuated at 25°C. On the other hand, relaxations caused by nicotine and exogenous NO were not significantly attenuated but were prolonged by cooling to 25°C. The responses associated with nerve stimulation by electrical pulses or nicotine were depressed by hypoxia (from about 500 mmHg of partial O₂ pressure to about 45 mmHg) under normothermia. However, hypothermia at 25°C prevented the inhibition by hypoxia of the neurogenic relaxation. It is concluded that the hypothermia-induced inhibition in the response to electrical nerve stimulation is not associated with a decreased synthesis and release of NO in vasodilator nerves nor with a reduced ability of smooth muscle to relax in response to NO. Interference with the propagation of action potentials might be involved in the inhibition via a fall of temperature. The fact that the hypoxia-induced impairment of vasodilator nerve function was prevented by cooling may partially explain the efficacy of hypothermia in protecting against ischemic neuronal injury in the brain. (Hypertens Res 2001; 24: 47-53)

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Angiotensin II (Ang II) has been shown to stimulate cardiac growth and collagen synthesis in cultured vascular smooth muscle cells and to increase fibroblast proliferation. Chronic infusion with Ang II increases blood pressure and activates growth mechanisms to produce hypertrophy of the heart. This study investigated the effects of an Ang II type 1 receptor antagonist, TCV-116, on preproendothelin-1 (preproET-1), ET_A receptor and platelet-derived growth factor (PDGF) A-chain expression in the left ventricle of Wistar-Kyoto rats treated for 2 weeks with Ang II (200ng·kg^-1·min^-1), and the relation of these effects to myocardial remodeling. Rats given Ang II alone (ANGII-V) were compared with rats also receiving TCV-116 (ANGII-TCV). In both groups, blood pressure was similar and significantly higher than in control rats. The preproET-1, ET_A receptor and PDGF A-chain expressions in the left ventricle were significantly increased in ANGII-V compared with control rats, and were significantly suppressed in ANGII-TCV compared with ANGII-V rats. ANGII-V rats showed a significant increase of the type I collagen expression, wall-to-lumen ratio, perivascular fibrosis, and myocardial fibrosis, with all these parameters being significantly improved by TCV-116. Myocardial remodeling in Ang II-induced hypertensive rats was significantly ameliorated by a subdepressor dose to TCV-116, which may have been due to a decrease in ET-1 and PDGF A-chain expression in the left ventricle. (Hypertens Res 2001; 24: 55-64)

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The aim of this study was to evaluate the acute effects of E-3174, a human active metabolite of the AT1 receptor antagonist, losartan, on hemodynamic functions in dogs with severe heart failure (HF). In dogs, insignificant plasma levels of E-3174 are present following administration of losartan, and therefore, the effects of these two drugs can be studied independently in the dog. HF was established by rapid pacing of the right ventricle (250-270 beats/min) for 4 weeks. We examined changes in cardiovascular functions after acute intravenous administration of losartan (1mg/kg) and E-3174 (0.3 and 1mg/kg), as well as an ACE inhibitor, enalapril (0.3 and 1mg/kg), under condition of HF. The HF before treatment was characterized by increases in pre- and after-load of the left ventricle (LV), consequent low cardiac output, and LV dilatation. E-3174 at 0.3 and 1mg/kg reduced pulmonary artery pressure (−13±6% and −22±3% from baseline, respectively, p<0.05), pulmonary capillary wedge pressure (−18±4% and −36±10%, p<0.05) and mean arterial pressure (−24±2% and −36±7%, p<0.05), increased stroke volume (SV: +12±7% p>0.05; +36±19%, p<0.05), and reduced peripheral resistance (−23±5% and −41±9%, p<0.05), but had no effect on the first derivative of left ventricular pressure (dP/dt/P) or the time constant for relaxation. Effects of losartan at 1mg/kg were similar to those of 0.3mg/kg of E-3174. Enalapril at 1mg/kg caused changes comparable to those seen after E-3174 administration (1mg/kg), except that the increase in SV (+16±8%, p<0.05) with enalapril was not as great as that with E-3174. Both losartan at 1mg/kg and E-3174 at 0.3 and 1mg/kg increased fractional shortening to a similar extent (FS: +52±12%, +47±8% and +56±8%), while enalapril at 0.3 and 1mg/kg had no significant effects on FS. Reflex elevation of plasma renin activity induced by 1mg/kg of E-3174 was similar to that caused by 1mg/kg of enalapril, suggesting that the two drugs achieved similar inhibition of the endogenous renin angiotensin system. Our study demonstrated that acute blockade of the AT1 receptor with E-3174 reduced elevated pre- and after-load and consequently increased stroke volume in a canine HF model. With the exception of changes in stroke volume, these effects of E-3174 were comparable to those produced by enalapril, and were 3 times stronger than those by losartan. (Hypertens Res 2001; 24: 65-74)

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Using Otsuka Long Evans Tokushima Fatty (OLETF) rats, a model of human non-insulin-dependent diabetes mellitus (NIDDM) that exhibits hypertension, obesity, hyperglycemia and hyperlipidemia, the role of local angiotensin II in cardiovascular complications at early stages of NIDDM was characterized. OLETF rats were given an angiotensin converting enzyme (ACE) inhibitor, cilazapril (10mg/kg/day) or vehicle from the age of 5 weeks to 20 weeks. Arteriolar, intermediate and venular capillary proportions were determined by the double-staining method and levels of collagen and non-collagenous proteins were determined by the selective dye-binding method in heart tissues. In OLETF rats at 20 weeks of age, capillary network remodeling (I.e., an increase in arteriolar portions and a decrease in venular portions) and an increase in collagen content were detected. Cilazapril not only exerted favorable effects on markers of diabetes, but also prevented capillary network remodeling and ameliorated the increase in collagen content. These results suggest that 1) capillary network remodeling and increase in extracellular matrix protein levels precede the onset of overt NIDDM in OLETF rats, and 2) angiotensin II may be involved in the pathogenesis of cardiac complications in the early stages of NIDDM. (Hypertens Res 2001; 24: 75-81)

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We report the case of a young pregnant woman with bilateral renovascular hypertension due to renal microaneurysms from an unknown cause, who had a successful delivery. Pregnancy did not affect the disease activity even in the postpartum period. Her blood pressure was maintained within the normal range by administration of labetalol. Although the angiographic appearance of the symmetrical aneurysms in both renal artery beds from the interlobular to arcuate artery levels suggested polyarteritis nodosa of multiple microaneurysms in the bilateral interlobular arteries, the clinical features suggested other causes of renovascular hypertension, such as fibromuscular dysplasia and/or congenital microaneurysms. We were thus unable to reach a definitive diagnosis. (Hypertens Res 2001; 24: 83-85)

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